Studies of P-glycoprotein Drug Interactions - Administrative Supplement for Undergraduate Summer Research

P-糖蛋白药物相互作用的研究 - 本科生暑期研究行政补充

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT (of the original funded project) P-glycoprotein (Pgp) is a molecular pump that detoxifies cells by transporting hundreds of structurally unrelated toxins out of the cell. Pgp limits uptake in the intestines, and enhances excretion of drugs in the liver, kidney and blood-brain barrier, of many drugs that are used for treatment of cancers, HIV/AIDS, psychiatric illnesses, and cardiovascular conditions. It is among the seven most important transporters responsible for regulating drug absorption and disposition that now require documentation of drug interactions for approval of any new drugs by the US Food and Drug Administration (FDA). Pgp is an ATP-binding cassette transporter with two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). It uses ATP hydrolysis to pump substrates across the cell membranes. Our recent X-ray structures of Pgp identified hydrophobic and aromatic amino acids that contribute to binding of different inhibitors to the drug-binding site. In this proposal, we will test the hypothesis that therapeutic drugs bind to different subsets of residues within defined subpockets in the TMDs of the protein. Our general approach is to introduce tryptophans (Trps) at strategic positions in order to monitor drug binding. The Trps will be introduced on the background of a new fully functional Trp-less Pgp, or a low-Trp Pgp that retains three native conformationally sensitive Trps in the cytoplasmic domains. Using fluorescence changes, such as quenching, and resonance energy transfer (FRET), we will map out sites of interaction of the purified protein with prototypical substrates that occupy biochemically defined and distinct binding sites, as well as those of common therapeutic drugs and newly identified inhibitors. We will further insert a fluorescent Trp analog (L-Anap) into wild-type Pgp using the amber stop codon suppression strategy to explore monitoring drug binding in biological cell membranes. By determining how drugs and inhibitors modulate the cooperativity and conformational dynamics of this multidomain transporter, we will gain unique insight into the mechanisms of drug binding and their effects on Pgp function. With these new approaches, we will address the molecular mechanism and kinetics of drug/inhibitor binding, determine synergistic effects, and refine the mechanisms of drug-drug interactions in Pgp. The information will pave the way to new analytical approaches to refine Pgp drug interaction studies of old and new drugs, and will be invaluable to redesign drugs with clinically favorable pharmacokinetics and accelerate pharmacotherapeutic developments.
项目摘要/摘要(原资助项目)

项目成果

期刊论文数量(0)
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INA L URBATSCH其他文献

INA L URBATSCH的其他文献

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{{ truncateString('INA L URBATSCH', 18)}}的其他基金

Studies of P-glycoprotein drug interactions
P-糖蛋白药物相互作用的研究
  • 批准号:
    10661486
  • 财政年份:
    2022
  • 资助金额:
    $ 0.75万
  • 项目类别:
Studies of P-glycoprotein drug interactions
P-糖蛋白药物相互作用的研究
  • 批准号:
    10366914
  • 财政年份:
    2022
  • 资助金额:
    $ 0.75万
  • 项目类别:
Studies of P-glycoprotein Drug Interactions - Administrative Supplement for Equipment Purchase
P-糖蛋白药物相互作用研究-设备采购行政补充
  • 批准号:
    10795338
  • 财政年份:
    2022
  • 资助金额:
    $ 0.75万
  • 项目类别:
Understanding polyspecific drug binding in P-glycoprotein
了解 P-糖蛋白中的多特异性药物结合
  • 批准号:
    8365444
  • 财政年份:
    2012
  • 资助金额:
    $ 0.75万
  • 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
  • 批准号:
    8152921
  • 财政年份:
    2010
  • 资助金额:
    $ 0.75万
  • 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
  • 批准号:
    8715824
  • 财政年份:
  • 资助金额:
    $ 0.75万
  • 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
  • 批准号:
    8306892
  • 财政年份:
  • 资助金额:
    $ 0.75万
  • 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
  • 批准号:
    8534191
  • 财政年份:
  • 资助金额:
    $ 0.75万
  • 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
  • 批准号:
    8379742
  • 财政年份:
  • 资助金额:
    $ 0.75万
  • 项目类别:

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